Our goal is to determine if we can "outpace" SIV transmission through the induction of a vaccine induced immune response in Rhesus macaques (RM). Two novel vaccines, the gp96-lg-SIV and the HPV-SIV will be administered through intraperitoneal (IP) and intravaginal routes respectively singly or in combination with and without SIV gp120. Our prior experience with these vaccines is that both elicit potent mucosal immune responses through different mechanisms. We hypothesize that the kinetics and nature of mucosal and systemic immune responses will determine the outcome of infection in vaccinated animals following vaginal SIV challenge. Innate and adaptive immune responses will be characterized for each observed outcome to get an understanding of correlates of immune protection. Immunologic studies will be enhanced by concomitant investigation of gene expression profiling, post translational modification, virus diversification and estimates of viral reservoir. Our goal is to understand how natural responses to SIV challenge are altered by vaccines that result in aborted SIV infection or attenuated virus dissemination and lowered peak viremia in vaccinated versus control animals. We are focusing on the vaginal local immunity as well as regional lymph nodes, gut and systemic immune responses. We propose the following aims to evaluate unvaccinated and vaccinated RM pre- and post- challenge with SIVmac251. Aim 1: to investigate innate immune responses, virus integration and virus reservoirs and Aim 2: to investigate adaptive immune responses of CD4 and CD8 T cells and B cells. Studies to be performed will include investigations post vaccination /pre-virus challenge, during the eclipse phase and at 60 days post virus challenge in vaccinated and unvaccinated animals. Exhaustive studies including host restriction factor Apobec3G, viral reservoir, virus diversification, NK cells, gamma-delta T cells, and adaptive SIV specific T and B cell phenotypic and functional profiles will be determined in a carefully coordinated and exhaustive analysis linking genomics, proteomics, histopathology and immunologic analyses to provide insight into earliest mechanisms of host- SIV interaction and correlates of vaccine incused immune protection.